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United States Patent (10) Patent No.: US 7,256.297 B2 Senanayake Et Al

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United States Patent (10) Patent No.: US 7,256.297 B2 Senanayake Et Al US007256297B2 (12) United States Patent (10) Patent No.: US 7,256.297 B2 Senanayake et al. (45) Date of Patent: Aug. 14, 2007 (54) METHODS OF PREPARING SULFINAMIDES 7,064.214 B2* 6/2006 Senanayake et al. ........ 546,339 AND SULFOXDES 7,129,378 B2 * 10/2006 Han et al. ................... 564,248 2005. O165240 A1 7/2005 Han et al. (75) Inventors: Chris Hugh Senanayake, Shrewsbury MA (US); Zhengxu Han,s Shrewsbury, s OTHER PUBLICATIONS MA (US); Dhilleepkumar Cogan, Derek A et al. Asymmetric Synthesis of Chiral Amines by Krishnamurthy, Westborough, MA Highly Diastereoselective 1.2-Additions of Organometallic (US); Derek Pflum, Northville, MI S. N-tert-Butanesulfinyl Imines. Tetrahedron 55 (1999) systers set Winon. Tang, Tony Pet al. The tert-Butanesulfinyl Group: An Ideal Chiral s Directing Group and Boc-Surrogate for the Asymmetric Synthesis (73) Assignee: Apsinterm, LLC., Wilmington,- DE appd Applicati CaOS O f beta-Aminoal-AO ACSAcids. J. Org.rg. Chem.Unem 1999, 64. (US) Liu, Guangcheng et al. Catalytic Asymmetric Synthesis of tert Butanesulfinamide. Application to the Asymmetric Synthesis of (*) Notice: Subject to any disclaimer, the term of this Amines. J. Am. Chem. Soc. 1997, 119, 9913-9914. patent is extended or adjusted under 35 Davis, Franklin A et al. Concise Asymmetric Synthesis of alpha U.S.C. 154(b) by 0 days. Amino Acid Derivatives from N-Sulfinylimino Esters. J. Org. Chem. 1999, 64, 3396-3397. (21) Appl. No.: 11/340,551 Cogan, Derek A. Catalytic Asymmetric Oxidation of tert-Butyl Disulfide. Synthesis of tert-Butanesulfinamides, tert-Butyl (22) Filed: Jan. 27, 2006 Sulfoxides and tert-Butanesulfinimines. Journal of the American Chemical Society, vol. 120, No. 32, Aug. 19, 1998. O O Owens, Timothy D et al. Synthesis, Utility and Structure of Novel (65) Prior Publication Data Bis(sulfinyl)imidoamidineis ony D et al, Syn Ligands for Asymmetric Lewis Acid US 2006/O128767 A1 Jun. 15, 2006 Catalysis. J. Am. Chem. Soc. 2001, 123, 1539-1540. Kagan, H. Betal. Some Routes to Chiral Sulfoxides with Very High Related U.S. Application Data Enantiomeric Excesses. Synlett 643-650, 1990. - - - Pflum, Derek A et al. Asymmetric Synthesis of Cetirizine (62) Division of application No. 10/120.541, filed on Apr. Dihydrochloride. Tetrahedron Letters 43 (2002) 923-926. 12, 2002, now Pat. No. 7,064,214. Wudl, Fetal, Novel Asymmetric Synthesis of Chiral Sulphoxides. J.C.S. Chem. C 1972, 61-62. (60) Provisional application No. 60/283,337, filed on Apr. Wudl, F ". Aynistric Synthesis of Chiral Sulfoxides. II. An 13, 2001. Intramolecular O -> N Sulfinyl Migration. Journal of the American (51) Int. Cl Chemical Society 95:19 Sep. 19, 1973. 6349-6358. nt. C. CO7D 291/04 (2006.01) * cited by examiner (52) U.S. Cl. ...................................................... 548/122 Primary Examiner Golam M. M. Shameem (58) Field of Classification Search ................. 548/122 (74) Attorney, Agent, or Firm—Martin A. Hay See application file for complete search history. (56) References Cited (57) ABSTRACT U.S. PATENT DOCUMENTS This invention encompasses novel methods of preparing Sulfinamides and Sulfoxides, particularly stereomerically 4,562,185 A 12/1985 Jager et al. 5,271,812 A 12/1993 Gao et al. pure sulfinamides and sulfoxides. The invention further 5,714,504 A 2/1998 Lindberg et al. encompasses novel compounds from which Sulfinamides 5,776,765 A 7, 1998 Graham et al. and Sulfoxides can be prepared. 5,945,425 A 8, 1999 Moormann et al. 5.948,789 A 9, 1999 Larsson et al. 15 Claims, No Drawings US 7,256.297 B2 1. METHODS OF PREPARING SULFNAMIDES AND SULFOXDES -continued e O R2 R2 This application is a divisional of application Ser. No. 5 S n 4 NHCI 10/120,541 filed on Apr. 12, 2002 now U.S. Pat. No. GE) uk uk" 7,064.214 the entirety of which is incorporated herein by N R - Mott - CIHN R reference, which application Ser. No. 10/120,541 claims priority to U.S. Provisional Application No. 60/283,337, filed Apr. 13, 2001. 10 Few methods of preparing enantiomerically pure Sulfina mides have been reported. See, e.g., Cogan, D. A., et al., J. 1. FIELD OF THE INVENTION Am. Chem. Soc. 120:8011-8019 (1998); Liu, G., et al., J. Am. Chem. Soc. 119:9913-9914 (1997). In one method, tert This invention relates to sulfinamides and sulfoxides, butanesulfinamide is prepared by asymmetrically oxidizing methods of their preparation, and compounds that can be 15 tert-butyl disulfide to provide an intermediate, which is then used to prepare them. cleaved by reaction with LiNH. Liu, G. et al., J. Am. Chem. Soc. 119:9913-9914 (1997). Unfortunately, the enantiomeric 2. BACKGROUND OF THE INVENTION purity of the resulting sulfinamide reportedly does not exceed 91%. Id. The method is further limited in that it can 2.1. THE ASYMMETRIC SYNTHESIS OF be used for the synthesis of only a few different kinds of AMINES sulfinamides, of which tert-butanesulfinamide is an example. In addition, this method is not amenable to large At least 75% of drugs and drug candidates reportedly scale, or industrial, production of Sulfinamides. A need incorporate amine functionality. Tang, T. P. and Ellman, J. 25 therefore exits for more efficient and effective methods of A. J. Org. Chem. 64:12-13 (1999). The asymmetric syn preparing a wide variety of Sulfinamides, particularly enan thesis of amines is consequently of particular importance to tiomerically pure sulfinamides. A need further exists for a the pharmaceutical industry. method of preparing sulfinamides that can be adapted to an One method that reportedly can be used to prepare industrial scale. optically active B-amino acids is disclosed in International 30 Application WO 2000/041997. According to this method, a 2.2. THE ASYMMETRIC SYNTHESIS OF compound of the formula RaC*H(OH) C*H(Rb)Rc, SULFOXIDES wherein Rc can be R1SO(R2)N—and theasterisk signifies a chiral center, is reportedly prepared by reacting an O-ami 35 The synthesis of chiral sulfoxides is also important to the nocarbonyl compound of the formula Ra—CO CH(Rb)— pharmaceutical industry. For example, a variety of pharma Rc with hydrogen or a hydrogen donor in the presence of an cologically active benzimidazoles and structurally related optically active transition metal compound and a base. Sulfoxide compounds contain a stereogenic Sulfur atom. Another recently reported method of preparing chiral Examples of Such compounds are shown below in racemic amino acids utilizes Sulfinamides. See, e.g., Tang, T. P. and 40 form: Ellman, J. A. J. Org. Chem. 64:12-13 (1999); Cogen, D. A., et al., Tetrahedron 55:8883-8904 (1999); Liu, G., et al., J. Am. Chem. Soc. 119:9913-9914 (1997); Davis, F. A. and FHCO McCoull, W., J. Org. Chem. 64:3396-3397 (1999). In an OCH example of this method, tert-butanesulfinamide condenses 45 with aldehydes and ketones to give tert-butanesulfinyl imi le OCH OUN S N 3 nes in high yields. Tang, T. P. and Ellman, J. A. J. Org. Na Chem. 64:12-13 (1999). These imines can then be contacted with Grignard reagents or organolithiums to provide the e N 2 intermediate shown below in Scheme I, which can then be 50 Pantoprazole sodium Subjected to acidic methanolysis to provide an a-branched amine-hydrochloride product. Id. CH3 N leS N OCH2CF H 55 e N 2 O R2 O= Lansoprazole S R CHO SN NH2 - N - 3 60 OUle CH OCH Oe R2 N l, N es G 2 CH3 65 Nis N R Omeprazole US 7,256.297 B2 3 4 imidazoles that comprise biohydrolyzable moieties such as -continued biohydrolyzable amides, biohydrolyzable esters, biohydro lyzable carbamates, biohydrolyzable carbonates, biohydro N CH3 ly Zable ureides, and biohydrolyzable phosphate analogues. OCsH11 5 Other examples of prodrugs include derivatives of 2-(2- N le N pyridylmethyl)suilfinyl)-benzimidazoles that comprise H i —NO, NO. —ONO, and —ONO, moieties. e Na2 As used herein, the terms “biohydrolyzable carbamate.” “biohydrolyzable carbonate.” “biohydrolyzable ureide.” Rabeprazole 10 "biohydrolyzatle phosphate’ mean a carbamate, carbonate, ureide, or phosphate, respectively, of a compound that either: 1) does not interfere with the biological activity of the Pantoprazole sodium is sold under the tradename Protonix(R) compound but can confer upon that compound advantageous for the short term treatment of erosive esophagitis associated properties in Vivo, Such as uptake, duration of action, or with gastroesophageal reflux disease (GERD). Physicians ' 15 onset of action; or 2) is biologically less active or inactive Desk Reference, 3439-3442 (55th ed., 2001). Lansoprazole but is converted in vivo to the biologically active compound. is sold under the tradename Prevacid R for the short term Examples of biohydrolyzable carbamates include, but are treatment of active duodenal ulcer. Id. at 3189-3194. Ome not limited to, lower alkylamines, substituted ethylenedi prazole, which is also indicated for the short term treatment amines, aminoacids, hydroxyalkylamines, heterocyclic and of active duodenal ulcer, is sold under the tradename heteroaromatic amines, and polyether amines. Prilosec(R). Id. at 587-591. Finally, rabeprazole is sold under As used herein, the term “biohydrolyzable ester” means the tradename Aciphex(R) for the short term treatment of an ester of a compound that either: 1) does not interfere with erosive or ulcerative GERD, for maintaining healing and the biological activity of the compound but can confer upon reduction in relapse rates of heartburn symptoms in patients that compound advantageous properties in vivo. Such as with erosive or ulcerative GERD, for the short-term healing 25 uptake, duration of action, or onset of action; or 2) is of active duodenal ulcer, and for the long-term treatment of biologically less active or inactive but is converted in vivo pathological hypersecretroy conditions.
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